1. Define IEM and understand what causes them. (p.505)
Inherited genetic mutation occuring within a gene coding for an enzyme that is required in a metabolic pathway. Faulty gene may result in enyzme with decreased functionality (mutations in AA sequences critical for function), decreased availability (reduced expression), or absence (no expression). IEMs can also arise secondary to defects in transport proteins.
2. General features and categories of IEMs. (p.506, 507)
Mode of inheritance
Predominantly autosomal recessive or x-linked recessive, but IEMs can have different forms with different modes of inheritance
Frequency
Individual IEM frequency is very rare but shear number of different types of IEMs makes up a significant incidence
Indivence varries based on gender and age
Early age of manifestation are typically more severe and rapidily progressing copared to later manifestations which are usually due to challenge by environmental factors.
Categorgies
Metabolism of:
Carbohydrates
Amino Acids
Organic Acids
Fatty Acids
Porphyrin
Purine/Pyrimidine
Steroid
Mitochondrial
Peroxisomal
Lysosomal
3. Typical clinical presentation. (p.508)
Because of variety of IEMs, nearly any presenting complaint can be caused by IEM, especially in childhood.
Consider IEM in any critically ill neonate See page 508 for complete details.
4. Newborn screening and appropriate diagnositic testing. (p.509)
Newborn screening for routine IEMs can allow for early detection/intervention through dietary modification/supplementation, etc. Screening typically for relatively common IEMs where analytical methodology is available for mass screening and for which effective therapy exists. Tandem mass spectometry is currently the prefered method for screending because it is fast and sensitive, able to process amny different compounds from a small blood sample.
5a. Understand hyperphenylalaninemia. (p.514-519)
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
phenylalanine-4-hydroxylase deficiency in classical presentation; can also be caused by defect in tetrahydrobiopterin (BH4) co-factor. Inability to convert phe to tyr, resulting in accumulating phe and phe metabolites.
Clinical Presentation
Irritability, eczema, musty odor from phenylalanine metabolites, increased muscle tone, active muscle tendon reflexes, mental retardation, seizures, microcephaly, decreased body growth
Treatment options or prevention
Dietary restriction of phenylalanine with possible BH4 and tyrosine supplements. Goal is to maintian phenylalanine at 2-10 mg/dL. Less severely affected patients can be challenged to determine if life-long dietary restriction is necessary.
5b. Understand homocysteinuria. (p.514-519)
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Classical form with defect in cystathionine synthase; can be caused by errors with methionine synthase and vitamin B12 or folate deficency. Inability to get rid of homocysteine by making cysteine or methionine.
Clinical Presentation
Delayed development, psychiatric symptoms, muscle weakness, mental retardation, osteoporosos, severe myopia and ectopia lentis (lens dislocation), thromboembolic complciations of CNS and pulmonary emboli.
Treatment options or prevention
Methionine-restricted, cysteine supplemented diet. Vitamin B6, Folate, betaine, or vitamin B12 at high doeses, depending on specific defect.
6a. Understand Galactosemias.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in ability to metabolize glucose:
(1) Galactose-1P uridyltransferase (most common)
(2) galactokinase
(3) uridine diphospho hexose 4-epimerase
Defect results in accumulation of glaactose which is converted to galactitol, a toxic metabolite.
Clinical Presentation
Onset during breast feeding with hypotonia, jaundice, lethargy, seizures, enlarged liver, hypoglycemia, and cataracts from galactitol buildup.
Treatment options or prevention
Prescribe glactose free diet, restrict milk intake throughout life.
6b. Understand Medium Chain Acyl CoA Dehydrogenase Deficiency.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in metabolizing medium chain fatty acids cused by errors anywhere in the fatty acid metabolism pathway:
acyl-CoA processing (defect in acyl-CoA dehydrogensase, enoyl-CoA hydratise, beta-hydroxylacyl-CoA dehydrogenase, and beta-ketoacyl-CoA transferase
Clinical Presentation
Present hypoglycemia due to continued glucose consumption during fasting because of inability to switch to fat resources to make ketone bodies. Excretion of carnitine in urine in effort to conserve CoA by substituting carnitine for CoA. Monocarboxylic fatty acids and dicarboxylic organic caids fromed by omega-oxidation since beta-oxidation not working. Hyperammonemia accounting for lethargy and coma, cumulating to cerebral edema.
Symptoms may not be present in frequently fed infant because of decreased reliance on secondary fuel sources during fasting -- typically symptoms occur when feeding is reduced and less frequent.
Treatment options or prevention
Avoid fasting, increase carbohydrates and amino acids in diet and reduce fat intake.
6c. Understand Inherited hyperammonemia.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in urea cycle caused most commonly by argininosuccinate lyase which converts argininosuccinate to arginine and fumurate. can also be caused by problems with argininosuccinate synthetase, glutamate synthase, ornithine transcarbamylase, and carbamyl phosphate synthase I. Errors in di-basic amino acid transport can also result in disruption.
Clinical Presentation
Hyperammonemia, poor growth, anorexia, hypothermia, papilledema (swelling optic disc), hepatomegaly, disdiadochokinesia (can't do repetative motions), etc. (see p.530)
Treatment options or prevention
Cessation of protein intake, increase non-protein caloric intake. Hemodialysis, i.v. sodium phenylbutyrate/benzoate. Supplement with arginine for patients with arginosuccinic aciduria (mild form of hyperammonemia).
6d. Understand Mucopolysaccharidoses.
Mode of Inheritance
Autosomal recessive except Hunter's syndrome which is x-linked recessive
Underlying metabolic defect and altered metabolites
Mucopolysaccharides not degraded by defective lysosomal enzymes (iduronidase, etc.) resulting in accumulation of heparan, dermatan, and keratan sulfates.
Clinical Presentation
Multiple organ systems may be involved depending on which disease.
CNS - hydorcephalus (defect in CSF reabsorption), mental retardation
Cardiovascular disease - angina-type symptoms secondary to arteriosclerosis and ischemia
Pulminary disease - obstructive airway disease
Ophthalmologic disease - corneal clouding, glaucoma
Muscularskeletal disease - short stature, joint stiffness
(see p. 533)
Treatment options or prevention
Bone marrow transplantation has some positive effects ni reducing hepatosplenomegaly, airway obstruction, and cardiopulmonary disease to allow survival past first decade of life. Most patients die in infancy.
Objectives
1. Define IEM and understand what causes them. (p.505)
Inherited genetic mutation occuring within a gene coding for an enzyme that is required in a metabolic pathway. Faulty gene may result in enyzme with decreased functionality (mutations in AA sequences critical for function), decreased availability (reduced expression), or absence (no expression). IEMs can also arise secondary to defects in transport proteins.
2. General features and categories of IEMs. (p.506, 507)
Mode of inheritance
Predominantly autosomal recessive or x-linked recessive, but IEMs can have different forms with different modes of inheritance
Frequency
Categorgies
Metabolism of:
3. Typical clinical presentation. (p.508)
Because of variety of IEMs, nearly any presenting complaint can be caused by IEM, especially in childhood.
Consider IEM in any critically ill neonate See page 508 for complete details.
4. Newborn screening and appropriate diagnositic testing. (p.509)
Newborn screening for routine IEMs can allow for early detection/intervention through dietary modification/supplementation, etc. Screening typically for relatively common IEMs where analytical methodology is available for mass screening and for which effective therapy exists. Tandem mass spectometry is currently the prefered method for screending because it is fast and sensitive, able to process amny different compounds from a small blood sample.
5a. Understand hyperphenylalaninemia. (p.514-519)
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
phenylalanine-4-hydroxylase deficiency in classical presentation; can also be caused by defect in tetrahydrobiopterin (BH4) co-factor. Inability to convert phe to tyr, resulting in accumulating phe and phe metabolites.
Clinical Presentation
Irritability, eczema, musty odor from phenylalanine metabolites, increased muscle tone, active muscle tendon reflexes, mental retardation, seizures, microcephaly, decreased body growth
Treatment options or prevention
Dietary restriction of phenylalanine with possible BH4 and tyrosine supplements. Goal is to maintian phenylalanine at 2-10 mg/dL. Less severely affected patients can be challenged to determine if life-long dietary restriction is necessary.
5b. Understand homocysteinuria. (p.514-519)
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Classical form with defect in cystathionine synthase; can be caused by errors with methionine synthase and vitamin B12 or folate deficency. Inability to get rid of homocysteine by making cysteine or methionine.
Clinical Presentation
Delayed development, psychiatric symptoms, muscle weakness, mental retardation, osteoporosos, severe myopia and ectopia lentis (lens dislocation), thromboembolic complciations of CNS and pulmonary emboli.
Treatment options or prevention
Methionine-restricted, cysteine supplemented diet. Vitamin B6, Folate, betaine, or vitamin B12 at high doeses, depending on specific defect.
6a. Understand Galactosemias.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in ability to metabolize glucose:
(1) Galactose-1P uridyltransferase (most common)
(2) galactokinase
(3) uridine diphospho hexose 4-epimerase
Defect results in accumulation of glaactose which is converted to galactitol, a toxic metabolite.
Clinical Presentation
Onset during breast feeding with hypotonia, jaundice, lethargy, seizures, enlarged liver, hypoglycemia, and cataracts from galactitol buildup.
Treatment options or prevention
Prescribe glactose free diet, restrict milk intake throughout life.
6b. Understand Medium Chain Acyl CoA Dehydrogenase Deficiency.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in metabolizing medium chain fatty acids cused by errors anywhere in the fatty acid metabolism pathway:
Clinical Presentation
Present hypoglycemia due to continued glucose consumption during fasting because of inability to switch to fat resources to make ketone bodies. Excretion of carnitine in urine in effort to conserve CoA by substituting carnitine for CoA. Monocarboxylic fatty acids and dicarboxylic organic caids fromed by omega-oxidation since beta-oxidation not working. Hyperammonemia accounting for lethargy and coma, cumulating to cerebral edema.
Symptoms may not be present in frequently fed infant because of decreased reliance on secondary fuel sources during fasting -- typically symptoms occur when feeding is reduced and less frequent.
Treatment options or prevention
Avoid fasting, increase carbohydrates and amino acids in diet and reduce fat intake.
6c. Understand Inherited hyperammonemia.
Mode of Inheritance
Autosomal recessive
Underlying metabolic defect and altered metabolites
Defect in urea cycle caused most commonly by argininosuccinate lyase which converts argininosuccinate to arginine and fumurate. can also be caused by problems with argininosuccinate synthetase, glutamate synthase, ornithine transcarbamylase, and carbamyl phosphate synthase I. Errors in di-basic amino acid transport can also result in disruption.
Clinical Presentation
Hyperammonemia, poor growth, anorexia, hypothermia, papilledema (swelling optic disc), hepatomegaly, disdiadochokinesia (can't do repetative motions), etc. (see p.530)
Treatment options or prevention
Cessation of protein intake, increase non-protein caloric intake. Hemodialysis, i.v. sodium phenylbutyrate/benzoate. Supplement with arginine for patients with arginosuccinic aciduria (mild form of hyperammonemia).
6d. Understand Mucopolysaccharidoses.
Mode of Inheritance
Autosomal recessive except Hunter's syndrome which is x-linked recessive
Underlying metabolic defect and altered metabolites
Mucopolysaccharides not degraded by defective lysosomal enzymes (iduronidase, etc.) resulting in accumulation of heparan, dermatan, and keratan sulfates.
Clinical Presentation
Multiple organ systems may be involved depending on which disease.
CNS - hydorcephalus (defect in CSF reabsorption), mental retardation
Cardiovascular disease - angina-type symptoms secondary to arteriosclerosis and ischemia
Pulminary disease - obstructive airway disease
Ophthalmologic disease - corneal clouding, glaucoma
Muscularskeletal disease - short stature, joint stiffness
(see p. 533)
Treatment options or prevention
Bone marrow transplantation has some positive effects ni reducing hepatosplenomegaly, airway obstruction, and cardiopulmonary disease to allow survival past first decade of life. Most patients die in infancy.